Suddenly occurring new-type viral infectious disease is a type of highly infectious and harmful disease resulted from self-evolution or self-variation of virus. Since its pathogen has an entirely new biological structure, the disease is generally difficult to prevent and treat at its outbreak, and thus causes a very serious hazard. Influenza virus, due to its high variability and the susceptibility of human body thereto, becomes an important source for suddenly occurring new-type viral infectious disease. At regular intervals, new-type influenza will become widely pandemic in humankind. In recent 100 years, there have been at least four times of outbreak of influenza, among which the influenza pandemic in 1918 killed almost twenty millions of people around the world. At present, H5N1 type high pathogenic avian influenza is pervading in poultry, and this influenza, along with the discontinuous variation in itself, will necessarily become a new type of influenza that can infect humankind. As the threat of an outbreak of influenza is drawing near, it is a very important means to develop in time a high-efficiency drug for dealing with the prevalence of suddenly occurring new-type viral infectious disease led by new-type influenza.
Neuraminidase (NA) is a key protein that promotes the separation and diffusion of influenza virus particles as newly formed from infected cells. Among the three types of proteins (hemagglutinin, HA, neuraminidase, NA and nonstructural protein NS 1) that are the easiest variable on the surface of influenza virus, NA is relatively stable, and in particular, the amino acid sequences thereof that constitute active sites are highly conservative in all influenza A and B viruses. Therefore, the development of an NA inhibitor is the optimal choice for dealing with unknown influenza virus. As far as the drugs for preventing and treating new type of influenza are concerned, NA inhibitors represented by oseltamivir and zanamivir are regarded as potential effective drugs. However, the two drugs both have certain limitations. Both of them are oral preparations, are unfavorable for treating high risk patients, and are also inconvenient to take by susceptible population such as elderly person and children, so their effects of prevention and treatment are greatly limited. As for other serious viral infectious diseases, there aren't effective drugs to prevent and treat them as well, and the expense for treating them is high. Moreover, the large and wide use of a single type of drug easily leads to the occurrence of drug-resistant virus stains, so that the drug prevention and treatment system will lose its protection ability. Therefore, it is necessary to continuously search for a new therapeutic route to thereby develop a drug having good therapeutic effect and low toxic-side effect.
(1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid [RWJ270201, BCX1812, JNJ2, peramivir] is a type of cyclopentane compound that is completely different in structure from oseltamivir and zanamivir, and can selectively inhibit NA of influenza A and B viruses. In vitro activity study showed that RWJ270201 could selectively inhibit in vitro the activity of NA of 7 influenza A virus stains (IC50=0.1-1.4 nM), and the activity of NA of 4 influenza B virus strains (IC50=0.6-11 nM) (Bania S., Parker C. D., Ananth S. L., et al, Comparison of the Anti-influenza Virus Activity of RWJ270201 against Clinical Isolates of Influenza Virus and Neuraminidase Inhibitor-Resistant Variants, Antimicrob Agents Chemother, 2001, 45(12), 3403-3408). The activity of RWJ270201 was equivalent to or higher than that of oseltamivir and zanamivir. In vivo activity study showed that RWJ270201 could markedly reduce the death rate of mice that were infected with influenza virus strain A/HongKong/156/97 (H5N1), resulting in a survival rate of up to 70% in the group of 0.1 mg/kg/day, and a survival rate of up to 100% in the group of 10 mg/kg/day, and could markedly reduce virus titer in lung tissue, and prevent the diffusion of virus to brain tissue (Govorkova E. A., Leneva I. A., Goloubeva O. G., et al., Comparison of Efficiencies of RWJ270201, Zanamivir, and Oseltamivir against H5N1, H9N2, and Other Avian Influenza Viruses, Antimicrob Agents Chemother, 2001, 45(10), 2723-2732). RWJ270201 could also inhibit lung consolidation and virus titer in lung tissue at the 6th day, and acted for a longer period of time than oseltamivir. This compound could still prevent the reduction in arterial oxygen saturation at a dose as low as 1 mg/kg/day. RWJ270201 (1 mg/kg/day) could also reduce the death rate, inhibit lung consolidation and prevent the reduction in arterial oxygen saturation of laboratory animals infected with lethal influenza virus strain B/Hong Kong/5/72, and was more effective than oseltamivir. In addition, RWJ270201 at a dose of 10 mg/kg/day could also effectively antagonize the infection with lethal influenza virus strain A/Bayern/07/95 (H1N1), and reduce the death rate of laboratory animals infected with influenza virus strain A/NWS/33 (H1N1) (Bantia S., Amold C. S., Parker C. D., Anti-influenza Virus Activity of Peramivir in Mice with Single Intramuscular Injection, Antiviral Research, 2006, 69(1), 39-45). RWJ270201 had a low toxicity, and was non-toxic to cells at a dose as high as 328 μg/ml; no toxic side effect was found when RWJ270201 was administered to rats at a dose of 1000 mg/kg/day for 5 days. No acute toxic reaction was observed when the dose administered to mice and rats was up to 3000 mg/kg/day (Sidwell R. W., Smee D. F., Huffman J. H., et al., In the fluenza of Virus Strain, Challenge Dose, and Time of Therapy Initiation on the in vivo Influenza Inhibitory Effect of RWJ270201, Antiviral Res., 2001, 51(3), 179-187). RWJ270201 is a new kind of high-efficiency and low-toxicity NA inhibitor.
However, as shown by study, RWJ270201 is easily hygroscopic, and it is difficult to completely remove water therein after absorbing moisture, thus the anhydrous form of RWJ270201 is difficult to obtain in industry, and the quality thereof is difficult to effectively control. RWJ270201 is unstable in aqueous solution, is easy to self-degrade under the influence of environmental factors, and is difficult to directly prepare into an injection for treating severe patients. The object of the invention is just for searching for (1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid derivative which is not easily hygroscopic and is controllable in quality and a method for preparing the same, and simultaneously developing a corresponding injection for treating severe patients.